Annonaceous acetogenins are a well established class of natural compounds that have been isolated from plants in the Annonaceae family. It has been reported that various members of this class of compounds exhibit significant bioactivities. Acetogenins are C.sub.35 -C.sub.39 compounds that typically contain two long hydrocarbon chains, one of which connects a terminal 2,4-disubstituted-.gamma.-lactone to a variable number of tetrahydrofuran (THF) rings. The hydrocarbon chains contain a number of oxygenated moieties which can be hydroxyls, acetoxyls and/or ketones. Recently, single-ring acetogenins containing double bonds, epoxide compounds which lack THF rings and a compound lacking both epoxides and THF rings have been reported. These interesting newer compounds support the proposed polyketide origin of the Annonaceous acetogenins and provide additional clues to their biogenesis.
All acetogenins found to date contain multiple stereocenters, the elucidation of which often presents daunting stereochemical problems. Because of their waxy nature, the acetogenins do not produce crystals suitable for X-ray crystallographic analysis. Relative stereochemistries of ring junctions have typically been determined by comparison of natural compounds with synthetic model compounds and such methods have proven to be invaluable with the acetogenins. Recently, the absolute stereochemistries of the carbinol centers of acetogenins have been determined with the help of synthetic model compounds and high field nuclear magnetic resonance (NMR) analysis of their methoxyfluoromethylphenylacetic acid (MPTA) esters (Mosher esters).
Most Annonaceous acetogenins are potently bioactive, but the mode of action of these compounds was unknown until Londerhausen et al. concluded in Pesticide Science 427-438 (1991), that they act to inhibit complex I of mitochondrial oxidative phosphorylation with an activity several times that of rotenone.
The present invention is directed to the isolation and characterization of the bioactivity of novel acetogenins. More particularly the present invention is directed to three new mono-tetrahydrofuran (THF) ring acetogenins each of which were isolated from the bark of Annona squamosa. These compounds each bear two hydroxyls that flank the THF ring and a carbonyl group at the C-9 position. The compounds were isolated using the brine shrimp lethality assay as a guide for the bioactivity-directed fractionation. It has been discovered that acetogenins possessing a hydroxyl flanking mono-THF system with a carbonyl in the aliphatic chain exhibit high selective cytotoxicity to various tumor cells and thus can be used to prepare chemotherapy compositions for administrations to patients having tumors.